We have previously demonstrated that human B lymphoid leukemias and lymphomas are monoclonal neoplasms which, although arrested during development, retain a finite capacity to differentiate when appropriately activated. These investigations allowed us to uncover the natural clonal evolution of follicular lymphoma in vivo by the use of anti-idiotype antibody. We have further identified the frequency of occurrence and mechanism of tumor clonal evolution in human lymphoid neoplasms. By thorough restriction mapping of rearranged genes in B-cell lymphomas, we have discovered frequent clonal evolution during the course of disease. Genetic changes were a consequence of secondary effects such as deletion, switching or somatic mutation. Specifically, we found no evidence of second primary neoplasms (biclonality). Despite frequent alterations of immunoglobulin gene loci, the bcl-2 gene, involved in direct fusion to the JH gene in the t(14;18) translocation, remains conserved and showed no restriction fragment size changes.